This application relates to compounds and compositions for treating diseases associated with cysteine protease activity, particularly diseases associated with activity of cathepsins B, K, L or S.
Cysteine proteases represent a class of peptidases characterized by the presence of a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are associated with the normal degradation and processing of proteins. The aberrant activity of cysteine proteases, e.g., as a result of increase expression or enhanced activation, however, may have pathological consequences. In this regard, certain cysteine proteases are associated with a number of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy and others. For example, increased cathepsin B levels and redistribution of the enzyme are found in tumors; thus, suggesting a role for the enzyme in tumor invasion and metastasis. In addition, aberrant cathepsin B activity is implicated in such disease states as rheumatoid arthritis, osteo arthritis, pneumocystis caninii, acute pancreatitis, inflammatory airway disease and bone and joint disorders.
The prominent expression of cathepsin K in osteoclasts and osteoclast-related multinucleated cells and its high collagenolytic activity suggest that the enzyme is involved in ososteoclast-mediated bone resorption and, hence, in bone abnormalities such as occurs in osteoporosis. In addition, cathepsin K expression in the lung and its elastinolytic activity suggest that the enzyme plays a role in pulmonary disorders as well.
Cathepsin L is implicated in normal lysosomal proteolysis as well as several disease states, including, but not limited to, metastasis of melanomas. Cathepsin S is implicated in Alzheimer""s disease and certain autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves"" disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto""s thyroiditis; allergic disorders, including, but not limited to asthma; and allogeneic immune responses, including, but not limited to, rejection of organ transplants or tissue grafts.
In view of the number of diseases wherein it is recognized that an increase in cysteine protease activity contributes to the pathology and/or symptomatology of the disease, molecules which are shown to inhibit the activity of this class of enzymes, in particular molecules which are inhibitors of cathepsins B, K, L and/or S, will be useful as therapeutic agents.
This Application relates to protease inhibitors of Formula I: 
in which:
X1 is a bond or a divalent group of Formula (a) or (b): 
xe2x80x83wherein:
X2 and X3 independently are xe2x80x94C(O)xe2x80x94 or xe2x80x94CH2S(O)2xe2x80x94;
R7 and R8 are independently (i) (C1-6)alkyl optionally substituted with cyano, halo, nitro, xe2x80x94NR10R10, xe2x80x94NR10C(O)OR10, xe2x80x94NR10C(O)NR10R10, xe2x80x94NR10C(NR10)NR10R10, xe2x80x94OR10, xe2x80x94SR10, xe2x80x94C(O)OR10, xe2x80x94C(O)NR10R10, xe2x80x94S(O)2NR10R10, xe2x80x94P(O)(OR10)OR10, xe2x80x94OP(O)(OR10)OR10, xe2x80x94NR10C(O)R11, xe2x80x94S(O)R11, xe2x80x94S(O)2R11, xe2x80x94C(O)R11, xe2x80x94OR12, xe2x80x94SR12, xe2x80x94S(O)R12, xe2x80x94S(O)2R12, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94OC(O)R12, xe2x80x94NR12R13, NR13C(O)R12, xe2x80x94NR13C(O)OR2, xe2x80x94C(O)N12R13, xe2x80x94S(O)2NR12R13, xe2x80x94NR13C(O)NR12R13 or xe2x80x94NR13C(NR13)NR12R13, wherein R10 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl, R11 is (C1-6)alkyl or halo-substituted (C1-3)alkyl, R12 is (C3-12)cycloalkyl(C0-3)alkyl, hetero(C3-12)cycloalkyl(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl or hetero(C5-12)aryl(C0-3)alkyl and R13 is hydrogen or (C1-6)alkyl, and wherein within R12 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from xe2x80x94R14, xe2x80x94X4OR14, xe2x80x94X4SR14, xe2x80x94X4S(O)R14, xe2x80x94X4S(O)2R14, xe2x80x94X4C(O)R14, xe2x80x94X4C(O)OR14, xe2x80x94X4OC(O)R14, xe2x80x94X4NR14R15, xe2x80x94X4NR15C(O)R14, xe2x80x94X4NR15C(O)OR14, xe2x80x94X4C(O)NR14R15, xe2x80x94X4S(O)2NR14R15, X4NR15C(O)NR14R15 or xe2x80x94X4NR15C(NR15)NR14R15, wherein X4 is a bond or (C1-6)alkylene, R14 is hydrogen or (C1-6)alkyl and R15 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl, or (ii) (C3-12)cycloalkyl(C0-3)alkyl, heterocyclo(C3-12)alkyl(C0-3)alkyl, (C6-12)aryl(C0-3)alkyl, hetero(C5-12)aryl(C0-3)alkyl, (C9-12)polycycloaryl(C0-3)alkyl or hetero(C8-12)polycycloaryl(C0-3)alkyl, wherein within R15 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from xe2x80x94R14, xe2x80x94X4OR14, xe2x80x94X4SR14, xe2x80x94X4S(O)R14, xe2x80x94X4S(O)2R14, xe2x80x94X4C(O)R14, xe2x80x94X4C(O)OR14, xe2x80x94X4OC(O)R14, xe2x80x94X4NR14R15, xe2x80x94X4NR15C(O)R14, xe2x80x94X4NR15C(O)OR14, xe2x80x94X4C(O)NR14R15, xe2x80x94X4S(O)2NR14R15, xe2x80x94X4NR15C(O)NR14R15 or xe2x80x94X4NR15C(NR15)NR14R15, wherein X4, R14 and R15 are as defined above; wherein within R7 and/or R8 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X4NR10R10, xe2x80x94X4NR10C(O)OR10, xe2x80x94X4NR10C(O)NR10R10, xe2x80x94X4NR10C(NR10)NR10R10, xe2x80x94X4OR10, xe2x80x94X4SR10, xe2x80x94X4C(O)OR10, xe2x80x94X4C(O)R10R10, xe2x80x94X4S(O)2NR10R10, xe2x80x94X4P(O)(OR4)OR10, xe2x80x94X4OP(O)(OR4)OR10, xe2x80x94X4NR10C(O)R11, xe2x80x94X4S(O)R11, xe2x80x94X4S(O)2R11 and xe2x80x94X4C(O)R11, wherein X4 is a bond or (C1-6)alkylene and R10 and R11 are as defined above, or
R7 taken together with R5 and/or R8 taken together with R6 forms trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo;
R9 at each occurrence is hydrogen or (C1-6)alkyl; and
R5 and R6 are independently hydrogen, (C1-6)alkyl or as defined above; and
R1 is xe2x80x94X6X7R16, wherein X6 is xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)C(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94, X7 is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR17xe2x80x94, wherein R17 is hydrogen or (C1-6)alkyl, and R16 is (i) (C16)alkyl optionally substituted by cyano, halo, nitro, xe2x80x94NR10R10, xe2x80x94NR10C(O)OR10, xe2x80x94NR10C(O)NR10R10, xe2x80x94NR10C(NR10)NR10R10, xe2x80x94OR10, xe2x80x94SR10, xe2x80x94C(O)OR10, xe2x80x94C(O)NR10R10, xe2x80x94S(O)2NR10R10, xe2x80x94P(O)(OR10)OR10, xe2x80x94OP(O)(OR10)OR10, xe2x80x94NR10C(O)R11, xe2x80x94S(O)R11, xe2x80x94S(O)2R11, xe2x80x94C(O)R11, xe2x80x94OR18, xe2x80x94SR18, xe2x80x94S(O)R18, xe2x80x94S(O)2R18, xe2x80x94C(O)R18, xe2x80x94C(O)OR18, xe2x80x94C(O)NR18R19, xe2x80x94NR18R19, xe2x80x94NR19C(O)R18, xe2x80x94NR19C(O)OR18, xe2x80x94NR19C(O)NR18R19 or xe2x80x94NR19C(NR19)NR18R19, wherein R10 and R11 are as defined above, R18 is (C3-12)cycloalkyl(C0-6)alkyl, hetero(C3-12)cycloalkyl(C0-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C5-12)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C8-12)polycycloaryl(C0-6)alkyl and R19 at each occurrence independently is hydrogen or (C1-6)alkyl, and wherein within R18 said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from xe2x80x94R14, xe2x80x94X4OR14, xe2x80x94X4SR14, xe2x80x94X4S(O)R14, xe2x80x94X4S(O)2R14, xe2x80x94X4C(O)R14, xe2x80x94X4C(O)OR14, xe2x80x94X4OC(O)R14, xe2x80x94X4N14R15, xe2x80x94X4NR15C(O)R14, xe2x80x94X4NR15C(O)OR14, xe2x80x94X4C(O)NR14R15, xe2x80x94X4S(O)2NR14R15, X4NR5C(O)NR14R15 or xe2x80x94X4NR15C(NR15)NR14R15, wherein X4, R14 and R15 are as defined above, or (ii) (C3-14)cycloalkyl(C0-6)alkyl, hetero(C3-14)cycloalkyl(C0-6)alkyl, (C6-14)aryl(C0-6)alkyl, diphenyl(C0-6)alkyl, hetero(C5-14)aryl(C0-6)alkyl, heterodi(C5-6)aryl(C0-6)alkyl, (C9-12)polycycloaryl(C0-6)alkyl or hetero(C9-14)polycyclo(C8-14)aryl(C0-6)alkyl, wherein said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, polycycloaryl or heterpolycycloaryl ring optionally is substituted by a group selected from xe2x80x94R14, xe2x80x94X4OR14, xe2x80x94X4SR14, xe2x80x94X4S(O)R14, xe2x80x94X4S(O)2R14, xe2x80x94X4C(O)R14, xe2x80x94X4C(O)R14, xe2x80x94X4OC(O)R14, xe2x80x94X4NR14R15, xe2x80x94X4NR15C(O)R14, xe2x80x94X4NR15C(O)OR14, xe2x80x94X4C(O)NR14R15, xe2x80x94X4S(O)2NR14R15R, xe2x80x94X4NR15C(O)R14R15 or xe2x80x94X4NR15C(NR15)NR14R15, wherein X4, R14 and R15 are as defined above; wherein within R1 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X4NR10R10, xe2x80x94X4NR10C(O)OR10, xe2x80x94X4NR10C(O)NR10R10, xe2x80x94X4NR10C(NR10)NR10R10, xe2x80x94X4OR10, xe2x80x94X4SR10, xe2x80x94X4C(O)OR10, xe2x80x94X4C(O)NR10R10, xe2x80x94X4S(O)2NR10R10, xe2x80x94X4P(O)(OR4)OR10, xe2x80x94X4OP(O)(OR4)OR10, xe2x80x94X4NR10C(O)R11, xe2x80x94X4S(O)R11, xe2x80x94X4S(O)2R11 and xe2x80x94X4C(O)R11, wherein X4, R10 and R11 are as defined above; or when X1 is a divalent group of Formula (a) or (b) then R1 may also represent hydrogen;
R2 is hydrogen or (C1-6)alkyl;
R3 is hydrogen or (C1-6)alkyl wherein said alkyl optionally is substituted with xe2x80x94OR20, xe2x80x94NR21C(O)OR20, xe2x80x94C(O)NR20R21, xe2x80x94S(O)20R21, wherein R20 is (C0-6)alkyl or (C6-10)aryl(C0-6)alkyl and R21 is hydrogen or (C1-6)alkyl, or (ii) (C6-10)aryl(C1-6)alkyl or (C5-10)heteroaryl(C1-6)alkyl or;
R3 taken together with R2 forms trimethylene, tetramethylene or phenylene-1,2-dimethylene, optionally substituted with hydroxy or oxo; wherein within R3 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X4NR10R10, xe2x80x94X4NR10C(O)OR10, xe2x80x94X4NR10C(O)NR10R10, xe2x80x94X4NR10C(NR10)NR10R10, xe2x80x94X4OR10, xe2x80x94X4SR10, xe2x80x94X4C(O)OR10, xe2x80x94X4C(O)NR10R10, xe2x80x94X4S(O)2NR10R10, xe2x80x94X4P(O)(OR4)OR10, xe2x80x94X4OP(O)(OR4)OR10, xe2x80x94X4NR10C(O)R11, xe2x80x94X4S(O)R11, xe2x80x94X4S(O)2R11 and xe2x80x94X4C(O)R11, wherein X4, R10 and R11 are as defined above; and
R4 is nitromethyl, 1-hydroxy-1-methylethyl or xe2x80x94CH2OR22, wherein R22 is hydrogen, (C1-6)alkyl, (C6-12)aryl(C0-6)alkyl, hetero(C8-12)polycycloaryl(C0-6)alkyl, (C1-6)alkylcarbonyl or (C6-12)arylcarbonyl wherein within R22 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X4NR10R10, xe2x80x94X4NR10C(O)OR10, xe2x80x94X4NR10C(O)NR10R10, xe2x80x94X4NR10C(NR10)NR10R10, xe2x80x94X4OR10, xe2x80x94X4SR10, xe2x80x94X4C(O)OR10, xe2x80x94X4C(O)NR10R10, xe2x80x94X4S(O)2NR10R10, xe2x80x94X4P(O)(OR4)OR10, xe2x80x94X4OP(OR4)OR10, xe2x80x94X4NR10C(O)R11, xe2x80x94X4S(O)R11, xe2x80x94X4S(O)2R11 and xe2x80x94X4C(O)R11, wherein X4, R10 and R11 are as defined above; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
A second aspect of this invention is a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, prodrug derivative, individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof in admixture with one or more suitable excipients.
A third aspect of this invention is a method of treating a disease in an animal in which inhibition of a cysteine protease can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula I or a N-oxide derivative, prodrug derivative, individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof.
A fourth aspect of this invention is the processes for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivative, protected derivatives, individual isomers and mixtures of isomers, and the pharmaceutically acceptable salts thereof as set forth in xe2x80x9cDetailed Description of the Inventionxe2x80x9d.
A fifth aspect of this invention is a process for preparing a compound of Formula II: 
in which R1 is peptidyl, R2 is hydrogen or (C1-6)alkyl, R3 is an amino acid side and R4 is (C1-6)alkyl or (C6-12)aryl(C1-6)alkyl.
Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the meanings given this Section:
xe2x80x9cAlicyclicxe2x80x9d means a moiety characterized by arrangement of the carbon atoms in closed non-aromatic ring structures having properties resembling those of aliphatics and may be saturated or partially unsaturated with two or more double or triple bonds.
xe2x80x9cAliphaticxe2x80x9d means a moiety characterized by straight or branched chain arrangement of the constituent carbon atoms and may be saturated or partially unsaturated with two or more double or triple bonds.
xe2x80x9cAlkenylxe2x80x9d means alkyl, as defined in this Application, provided that the radical is comprised of at least one double bond. Hence, optionally substituted (C2-6)alkenyl as used in this Application to define R3 includes 2-bromovinyl (xe2x80x94CHxe2x95x90CHBr), buta-1,3-dienyl (xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CH2), 2-chloro-1-methylpropenyl (xe2x80x94C(CH3)xe2x95x90CClxe2x80x94CH3), 2-chlorovinyl (xe2x80x94CHxe2x95x90CHCl), 4-isopropenyl (xe2x80x94C(CH3)xe2x95x90CH2), 1-methylpropenyl (xe2x80x94C(CH3)xe2x95x90CHxe2x80x94CH3), 2-methylpropenyl (xe2x80x94CHxe2x95x90C(CH3)2), 2-nitrovinyl (xe2x80x94CHxe2x95x90CHNO2), propenyl (xe2x80x94CHxe2x95x90CHxe2x80x94CH3), 2-trifluoromethylvinyl (xe2x80x94CHxe2x95x90CHxe2x80x94CF3), trifluorovinyl (xe2x80x94CF=CF2), vinyl (xe2x80x94CHxe2x95x90CH2), and the like).
xe2x80x9cAlkoxyxe2x80x9d means the radical xe2x80x94OR, wherein R is alkyl as defined in this Application, having the number of carbon atoms indicated (e.g., (C1-4)alkoxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethynyloxy, 1-propynyloxy, 2-propynyloxy, and the like).
xe2x80x9cAlkylxe2x80x9d represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having the number of carbon atoms indicated (e.g. (C1-6)alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl represented along with another radical (e.g. as in arylalkyl) means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond (e.g. (C6-12)aryl(C0-6)alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl 3-phenylpropyl, and the like).
xe2x80x9cAlkylenexe2x80x9d, unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g. (C1-6)alkylene includes methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2CH2xe2x80x94), trimethylene (xe2x80x94CH2CH2CH2xe2x80x94), 2-methyltrimethylene (xe2x80x94CH2CH(CH3)CH2xe2x80x94), tetramethylene (xe2x80x94CH2CH2CH2CH2xe2x80x94), 2-butenylene (xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94), 2-methyltetramethylene (xe2x80x94CH2CH(CH3)CH2CH2xe2x80x94), pentamethylene (xe2x80x94CH2CH2CH2CH2CH2xe2x80x94) and the like). For example, a group of Formula (a), wherein R11 is hydrogen and R12 taken together with R9 forms optionally substituted trimethylene is depicted by the following illustration: 
in which R is an optional hydroxy or oxo group and X3 and R1 are as defined in the Summary of the Invention for Formula I. Straight, saturated (C2-5)alkylene includes ethylene, trimethylene, tetramethylene and pentamethylene. For example, instances wherein R3 and R4 taken together form straight, saturated (C2-5)alkylene, wherein within said alkylene any one to two carbon atoms optionally is replaced by a heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR28xe2x80x94 wherein R28 is hydrogen or (C1-6)alkyl, may be represented by, but are not limited to, the following illustrations: 
wherein R2, R5, R6 and R28 are as defined in the Summary of the Invention for Formulae I and II.
xe2x80x9cAlkylidenexe2x80x9d means a straight or branched saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g. (C1-6)alkylidene includes methylene (xe2x95x90CH2), ethylidene (xe2x95x90CHCH3), isopropylidene (xe2x95x90C(CH3)2), propylidene (xe2x95x90CHCH2CH3), allylidene (xe2x95x90CHCHxe2x95x90CH2), and the like).
xe2x80x9cAminoxe2x80x9d means the radical xe2x80x94NH2. Unless indicated otherwise, the compounds of the invention containing amino moieties include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
xe2x80x9cAnimalxe2x80x9d includes humans, non-human mammals (e.g. dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, or the like) and non-mammals (e.g. birds, or the like).
xe2x80x9cArylxe2x80x9d means a monocyclic or bicyclic ring assembly (fused or linked by a single bond) containing the total number of ring carbon atoms indicated, wherein each ring is comprised of 6 ring carbon atoms and is aromatic or when fused with a second ring forms an aromatic ring assembly. For example, (C6-12)aryl as used in this Application to define R1 includes phenyl, naphthyl and biphenylyl.
xe2x80x9cAromaticxe2x80x9d means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4n+2.
xe2x80x9cCarbamoylxe2x80x9d means the radical xe2x80x94C(O)NH2. Unless indicated otherwise, the compounds of the invention containing carbamoyl moieties include protected derivatives thereof. Suitable protecting groups for carbamoyl moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cCarboxyxe2x80x9d means the radical xe2x80x94C(O)OH. Unless indicated otherwise, the compounds of the invention containing carboxy moieties include protected derivatives thereof. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like. For example, a compound of Formula I wherein R7 contains a carboxy moiety may exist as either the unprotected or a protected derivative, e.g. wherein R7 is methoxycarbonyl, and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cCycloalkylxe2x80x9d means a saturated or partially unsaturated, monocyclic ring, bicyclic ring assembly (directly linked by a single bond or fused) or bridged polycyclic ring assembly containing the number of ring member carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g. (C3-12)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclohexylyl, cyclopentylcyclohexyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthalenyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, and the like).
xe2x80x9cDiseasexe2x80x9d specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition which may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the xe2x80x9cside effectsxe2x80x9d of such therapy.
xe2x80x9cGuanidinoxe2x80x9d means the radical xe2x80x94NHC(NH)NH2. Unless indicated otherwise, the compounds of the invention containing guanidino moieties include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo or iodo.
xe2x80x9cHalo-substituted alkylxe2x80x9d, as a group or part of a group, means xe2x80x9calkylxe2x80x9d substituted by one or more xe2x80x9chaloxe2x80x9d atoms, as such terms are defined in this Application. Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g. halo-substituted (C1-3)alkyl includes chloromethyl, dicloromethyl, difluoromethyl, trifluromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the like).
xe2x80x9cHeteroarylxe2x80x9d means aryl, as defined herein, provided that one or more of the ring member carbon atoms indicated, is replaced by heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, wherein R is hydrogen, (C1-6)alkyl or a protecting group, and each ring contained therein is comprised of 5 to 6 ring member atoms. For example, hetero(C5-12)aryl as used in this Application includes benzofuryl, benzooxazolyl, benzothiazolyl, [2,4xe2x80x2]bipyridinylyl, carbazolyl, carbolinyl, chromenyl, cinnolinyl, furazanyl, furyl, imidazolyl, indazolyl, indolyl, indolizinyl, isobenzofuryl, isochromenyl, isooxazolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxazolyl, perimidinyl, 2-phenylpyridyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyradazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolizinyl, pyrrolidinyl, pyrrolyl, pyranyl, quinazolinyl, quinolizinyl, quinolyl, quinoxalinyl, tetrazolyl, thiazolyl, 4-thiazol-4-ylphenyl, thienyl, xanthenyl, and the like.
xe2x80x9cHeteroatom moietyxe2x80x9d includes xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, wherein R is hydrogen, (C1-6)alkyl or a protecting group.
xe2x80x9cHeterocycloalkylxe2x80x9d means cycloalkyl, as defined herein, provided that one or more of the ring member carbon atoms indicated is replaced by heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, wherein R is hydrogen, (C1-6)alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g. the term heterocyclo(C5-12)alkyl includes [1,4xe2x80x2]bipiperidinylyl, dihydrooxazolyl, morpholinyl, 1-morpholin-4-ylpiperidinyl, piperazinyl, piperidyl, pirazolidinyl, pirazolinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, and the like). Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like. For example, a compound of Formula I wherein R1 is piperidin-4-ylcarbonyl may exist as either the unprotected or a protected derivative, e.g. wherein R1 is 1-tert-butoxycarbonylpiperidin-4-ylcarbonyl, and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cHeteropolycycloarylxe2x80x9d means polycycloaryl, as defined herein, except one or more of the ring member carbon atoms indicated are replaced by a heteroatom moiety selected from xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, wherein R is hydrogen, (C1-6)alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof. For example, hetero(C8-12)polycycloaryl includes 1xe2x80x2,2xe2x80x2-dihydro-2H-[1,4xe2x80x2]bipyridinylyl, chromanyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, and the like.
xe2x80x9cHydroxyxe2x80x9d means the radical xe2x80x94OH. Unless indicated otherwise, the compounds of the invention containing hydroxy radicals include protected derivatives thereof. Suitable protecting groups for hydroxy moieties include benzyl and the like and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cIminoketone derivativexe2x80x9d means a derivative containing the moiety xe2x80x94C(NR)xe2x80x94, wherein R is hydrogen or (C1-6)alkyl.
xe2x80x9cIsomersxe2x80x9d mean compounds of Formula I having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed xe2x80x9cstereoisomersxe2x80x9d. Stereoisomers that are not mirror images of one another are termed xe2x80x9cdiastereomersxe2x80x9d and stereoisomers that are nonsuperimposable mirror images are termed xe2x80x9cenantiomersxe2x80x9d or sometimes xe2x80x9coptical isomersxe2x80x9d. A carbon atom bonded to four nonidentical substituents is termed a xe2x80x9cchiral centerxe2x80x9d. A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a xe2x80x9cracemic mixturexe2x80x9d. A compound that has more than one chiral center has 2nxe2x88x921 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as ether an individual diastereomer or as a mixture of diastereomers, termed a xe2x80x9cdiastereomeric mixturexe2x80x9d. When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g. see xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 3rd edition, March, Jerry, John Wiley and Sons, New York, 1985). It is understood that the names and illustration used in this Application to describe compounds of Formula I are meant to be encompassed all possible stereoisomers and any mixture, racemic or otherwise, thereof.
xe2x80x9cKetone derivativexe2x80x9d means a derivative containing the moiety xe2x80x94C(O)xe2x80x94.
xe2x80x9cNitroxe2x80x9d means the radical xe2x80x94NO2.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase xe2x80x9c(C1-6)alkyl optionally substituted with cyano, halo, nitro,xe2x80x9d means that the alkyl group referred to may or may not be substituted in order to fall within the scope of the invention.
xe2x80x9cOxaloxe2x80x9d means the radical xe2x80x94C(O)C(O)OH.
xe2x80x9cN-oxide derivativesxe2x80x9d means a derivatives of compound of Formula I in which nitrogens are in an oxidized state (i.e., O←N) and which possess the desired pharmacological activity.
xe2x80x9cOxoxe2x80x9d means the radical xe2x95x90O.
xe2x80x9cPathologyxe2x80x9d of a disease means the essential nature, causes and development of the disease as well as the structural and functional changes that result from the disease processes.
xe2x80x9cPeptidylxe2x80x9d means a peptide residue, for example, of the general formula: 
in which n is 1 or greater and each X2, X3, R1 and R5 are as defined in the Summary of the Invention for Formula I or any other peptide residue comprised of 1 or more contiguous natural or non-natural occurring amino acid moieties.
xe2x80x9cPharmaceutically acceptablexe2x80x9d means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d means salts of compounds of Formula I which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartatic acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic hi acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4xe2x80x2-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.
Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, ammonium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
xe2x80x9cPhenylene-1,2-dimethylenexe2x80x9d means the divalent radical xe2x80x94CH2C6H4CH2xe2x80x94, wherein the methylene moieties are attached at the 1- and 2-positions of the phenylene moiety. For example, a group of Formula (a), wherein X4 is xe2x80x94CHR12xe2x80x94 in which R12 together with R9 forms optionally substituted phenylene-1,2-dimethylene is illustrated by the following formula: 
in which R is an optional hydroxy group and X3 and R1 are as defined in the Summary of the Invention for Formulae I and II.
xe2x80x9cPolycycloarylxe2x80x9d means a bicyclic ring assembly (directly linked by a single bond or fused) containing the number of ring member carbon atoms indicated, wherein at least one, but not all, of the fused rings comprising the radical is aromatic, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g. (C9-12)polycycloaryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2-dihydronaphthalenyl, cyclohexylphenyl, phenylcyclohexyl, 2,4-dioxo-1,2,3,4-tetrahydronaphthalenyl, and the like).
xe2x80x9cProdrugxe2x80x9d means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula (I). For example an ester of a compound of Formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester of a compound of Formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of Formula (I) containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates. Suitable esters of compounds of Formula (I) containing a carboxy group, are for example those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, page 379. An especially useful class of esters of compounds of Formula (I) containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32, page 2503-2507, and include substituted (aminomethyl)-benzoates, for example, dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-benzoates, and (4-alkylpiperazin-1-yl)benzoates, e.g. 3- or 4-(4-alkylpiperazin-1-yl)benzoates.
xe2x80x9cProtected derivativesxe2x80x9d means derivatives of compounds of Formula I in which a reactive site or sites are blocked with protective groups. Protected derivatives of compounds of Formula I are useful in the preparation of compounds of Formula I or in themselves may be active cysteine protease inhibitors. A comprehensive list of suitable protective groups can be found in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc. 1981.
xe2x80x9cSulfamoylxe2x80x9d means the radical xe2x80x94S(O)2NH2. Unless indicated otherwise, the compounds of the invention containing sulfamoyl radicals include protected derivatives thereof. Suitable protecting groups for sulfamoyl radicals include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cTherapeutically effective amountxe2x80x9d means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
xe2x80x9cThioketone derivativexe2x80x9d means a derivative containing the moiety xe2x80x94C(S)xe2x80x94.
xe2x80x9cTreatmentxe2x80x9d or xe2x80x9ctreatingxe2x80x9d means any administration of a compound of the present invention and includes:
(1) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease,
(2) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or
(3) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
xe2x80x9cTrimethylenexe2x80x9d means the divalent radical xe2x80x94CH2CH2CH2xe2x80x94. For example, a group of Formula (a), wherein X3 is xe2x80x94CHR7xe2x80x94 in which R7 together with R1 forms optionally substituted trimethylene is illustrated by the following formula: 
in which R19 is an optional hydroxy or oxo group and X2 and R1 are as defined in the Summary of the Invention for Formula I.
xe2x80x9cUreidoxe2x80x9d means the radical xe2x80x94NHC(O)NH2. Unless indicated otherwise, the compounds of the invention containing ureido moieties include protected derivatives thereof. Suitable protective groups for ureido moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. For example, a compound of Formula I wherein the R1 contains an ureido radical may exist as either the unprotected or a protected derivative and both the unprotected and protected derivatives fall within the scope of the invention.
While the broadest definition of this invention is set forth in the Summary of the Invention, certain aspects of the invention are preferred. Preferred are compounds of Formula I in which:
X1 is a bond or a divalent group of Formula (a) wherein:
R5 is hydrogen or together with R7 forms phenylene-1,2-dimethylene; and
R7 is (i) (C1-6)alkyl optionally substituted with xe2x80x94OR10, xe2x80x94C(O)OR10, xe2x80x94C(O)NR10R10, wherein R10 at each occurrence independently is hydrogen or (C1-6)alkyl or (ii) (C6-12)aryl(C0-3)alkyl, cyclo(C3-12)alkyl(C0-3)alkyl or (C6-12)aryl(C0-3)alkyl or (iii) together with R5 is phenylenedimethylene; wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X4NR10R10, xe2x80x94X4NR10C(O)OR10, xe2x80x94X4NR10C(O)NR10R10, xe2x80x94X4NR10C(NR10)NR10R10, xe2x80x94X4OR10, xe2x80x94X4SR10, xe2x80x94X4C(O)OR10, xe2x80x94X4C(O)NR10R10, xe2x80x94X4S(O)2NR10R10, xe2x80x94X4P(O)(OR4)OR10, xe2x80x94X4OP(O)(OR4)OR10, xe2x80x94X4NR10C(O)R11, xe2x80x94X4S(O)R11, xe2x80x94X4S(O)2R11 and xe2x80x94X4C(O)R11, wherein X4 is a bond or (C1-6)alkylene, R10 at each occurrence independently is hydrogen, (C1-6)alkyl or halo-substituted (C1-3)alkyl and R11 is C1-6)alkyl or halo-substituted (C1-3)alkyl;
R1 is xe2x80x94X6X7R16, wherein X6 isxe2x80x94C(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94, X7 is a bond, xe2x80x94Oxe2x80x94 or xe2x80x94NR17xe2x80x94, wherein R17 is hydrogen or (C1-6)alkyl, and R16 is (i) (C1-6)alkyl optionally substituted with xe2x80x94C(O)OR10, xe2x80x94NR10R10 or xe2x80x94NR10C(O)OR10, wherein R10 at each occurrence independently is hydrogen or (C1-6)alkyl or (ii) hetero(C3-14)cycloalkyl(C0-6)alkyl, (C6-14)aryl(C0-6)alkyl, diphenyl(C0-6)alkyl, or hetero(C5-14)aryl(C0-6)alkyl; wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X4NR10R10, xe2x80x94X4NR10C(O)OR10, xe2x80x94X4NR10C(O)NR10R10, xe2x80x94X4NR10C(NR10)NR10R10, xe2x80x94X4OR10, xe2x80x94X4SR10, xe2x80x94X4C(O)OR10, xe2x80x94X4C(O)NR10R10, xe2x80x94X4S(O)2NR10R10, xe2x80x94X4P(O)(OR4)OR10, xe2x80x94X4OP(O)(OR4)OR10, xe2x80x94X4NR10C(O)R11, xe2x80x94X4S(O)R11, xe2x80x94X4S(O)R11, xe2x80x94X4S(O)2R11 and xe2x80x94X4C(O)R11, wherein X4, R10 and R11 are as defined above;
R2 is hydrogen;
R3 is (i) hydrogen or (C1-6)alkyl optionally substituted with xe2x80x94OR20, xe2x80x94NR21C(O)OR20, xe2x80x94C(O)NR20R21, xe2x80x94S(O)2R20, wherein R20 is (C0-6)alkyl or (C0-10)aryl(C0-6)alkyl and R21 is hydrogen or (C1-6)alkyl, or (ii) (C(6-10)aryl(C1-6)alkyl or (C5-10)heteroaryl(C1-6)alkyl or (ii) together with R2 forms trimethylene or phenylene-1,2-dimethylene; wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 5 radicals independently selected from (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, halo-substituted (C1-4)alkyl, nitro, xe2x80x94X4NR10R10, xe2x80x94X4NR10C(O)OR10, xe2x80x94X4NR10C(O)NR10R10, xe2x80x94X4NR10C(NR10)NR10R10, xe2x80x94X4OR10, xe2x80x94X4SR10, xe2x80x94X4C(O)OR10, xe2x80x94X4C(O)NR10R10, xe2x80x94X4S(O)2NR10R11, xe2x80x94X4P(O)(OR4)OR10, xe2x80x94X4OP(O)(OR4)OR10, xe2x80x94X4NR10C(O)R11, xe2x80x94X4S(O)R11, xe2x80x94X4S(O)2R11 and xe2x80x94X4C(O)R11, wherein X4, R10 and R11 are as defined above; and
R4 is nitromethyl, 1-hydroxy-1-methylethyl or xe2x80x94CH2OR22, wherein R22 is hydrogen, (C1-6)alkyl, (C6 12)aryl(C0-6)alkyl, heteropolycyclo(C8-12)aryl(C0-6)alkyl, (C1-6)alkylcarbonyl or (C6-12)arylcarbonyl, wherein within R4 any aromatic ring present may be substituted further by 1 to 3 radicals independently selected from halo, xe2x80x94OR10, xe2x80x94C(O)NR10R10, xe2x80x94S(O)2NR10R10 or xe2x80x94X4NR10R10, wherein X4, R10 and R11 are as defined above; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
Preferred are compounds of Formula I in which within Formula (a):
R5 is hydrogen or as defined below; and
R7 is (i) butyl, ethyl, methyl, 1-methylethyl, 1-methylpropyl or 2-methylpropyl optionally substituted with xe2x80x94OR10, xe2x80x94C(O)OR10, xe2x80x94NR10R10, xe2x80x94NR10C(O)OR10 or xe2x80x94C(O)NR10R10, wherein R10 is hydrogen or (C1-6)alkyl, or (ii) benzyl, benzyoxycarbonylmethyl, biphenyl-4-ylmethyl, cyclohexyl, cyclohexylmethyl, naphth-2-ylmethyl, phenylcarbamoylmethyl or phenylethyl or (iii) together with R5 is phenylenedimethylene; wherein within R7 any alicyclic or aromatic ring system present may be substituted further by 1 to 3 radicals independently selected from nitro and amino;
R1 is hydrogen, acetyl, 3-aminobenzoyl, 4-aminobutyryl, 3-aminopropionyl, 6-aminohexanoyl, 3-aminomethylbenzoyl, 4-aminomethylbenzoyl, benzoyl, benzylcarbamoyl, 4-benzyloxybenzoyl, benzyloxycarbonyl, tert-butoxycarbonyl, 3-tert-butoxycarbonylaminobenzoyl, 4-tert-butoxycarbonylaminobutyryl, 6-tert-butoxycarbonylaminohexanoyl, 3-tert-butoxycarbonylaminomethylbenzoyl, 4-tert-butoxycarbonylaminomethylbenzoyl, 1-tert-butoxycarbonylpiperidin-4-ylcarbonyl, 1-tert-butoxycarbonylpyrrolidin-2-ylcarbonyl, 3-carbamoylbenzoyl, 3-cyanobenzoyl, dibenzofur-2-ylsulfonyl, 3-[Nxe2x80x2,Nxe2x80x3-di(tert-butoxycarbonyl)guanidino]benzoyl, 4-dimethylaminobenzoyl, 2,2-dimethylpropionyl, 3-diphenylpropionyl, 3-fluorobenzoyl, 3-guanidinobenzoyl, 3-hydroxybenzoyl, 1H-indol-3-ylacetyl, 3-methoxycarbonylbenzoyl, 3-methoxycarbonylpropionyl, 3-methoxyphenylcarbamoyl 4-methylpiperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl, naphth-1-ylcarbonyl, naphth-2-ylcarbonyl naphth-2-ylsulfonyl, 3-nitrophenylacetyl, phenoxyacetyl, phenylcarbamoyl, 3-phenylpropionyl, piperidin-4-ylcarbonyl, 1-piperidin-1-ylpiperidin-1-ylcarbonyl, pyrid-3-ylacetyl, pyrid-4-ylacetyl, pyrid-3-ylcarbonyl, pyrid-4-ylcarbonyl, pyrrolidin-2-ylcarbonyl, pyrazinylcarbonyl or 3-ureidobenzoyl;
R2 is hydrogen or as defined below;
R3 is hydrogen, benzyl, 2-benzyloxyethyl, 4-benzyloxycarbonylaminobutyl, benzyloxymethyl, butyl, 2-(4-hydroxyphenyl)ethyl, 1H-indol-3-ylmethyl, 4-methoxybenzyl, methyl, 2-methylsulfonylethyl, 2-methylpropyl, phenethyl, 2-phenylcarbamoylethyl or together with R2 forms tetramethylene or phenylenedimethylene; and
R4 is acetoxymethyl, benzo[1,3]dioxol-5-yloxy, benzyloxymethyl, 4-carbamoylphenoxymethyl, 4-chlorophenoxymethyl, 2,5-dichlorobenzoyloxymethyl, 2,6-dichlorobenzoyloxymethyl, 3-dimethylaminophenoxymethyl, ethoxymethyl, hydroxymethyl, 1-hydroxy-1-methylethyl, 4-(1H-imidazol-1-yl)phenoxymethyl, methoxymethyl, 3-methoxyphenoxymethyl, 4-methoxyphenoxymethyl, 4-sulfamoylphenoxymethyl or phenoxymethyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
Preferred are compounds of Formula I in which within Formula (a), R5 is hydrogen and R7 is butyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl or naphth-2-ylmethyl; R1 is 3-aminobenzoyl, 3-aminomethylbenzoyl, 4-aminomethylbenzoyl, benzoyl, benzylcarbamoyl, benzyloxycarbonyl, tert-butoxycarbonyl, 3-tert-butoxycarbonylaminobenzoyl, 4-tert-butoxycarbonylaminomethylbenzoyl, 3-[Nxe2x80x2,Nxe2x80x3-di(tert-butoxycarbonyl)guanidino]benzoyl, 4-dimethylaminobenzoyl, 3-guanidinobenzoyl 4-methylpiperazin-1-ylcarbonyl, naphth-1-ylcarbonyl, naphth-2-ylcarbonyl or piperidin-4-ylcarbonyl; R2 is hydrogen; R3 is hydrogen, 4-benzyloxycarbonylaminobutyl, butyl or phenethyl; and R4 is benzyloxymethyl, hydroxymethyl, 2,5-dichlorobenzoyloxymethyl, ethoxymethyl, 1-hydroxy-1-methylethyl or phenoxymethyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers; and the pharmaceutically acceptable salts thereof.
The compounds of the invention are cysteine protease inhibitors, in particular the compounds of the invention inhibit the activity of cathepsins B, L, K and/or S and, as such, are useful for treating diseases in which cathepsin B, L, K and/or S activity contributes to the pathology and/or symptomatology of the disease. For example, the compounds of the invention are useful in treating tumor invasion and metastasis, in particular as anti-angiogenic agents, rheumatoid arthritis, osteo arthritis, pneumocystis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders. Furthermore, the compounds of the invention are useful in treating bone resorption disorders, e.g., osteoporosis. The compounds of the invention also are useful in treating autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves"" disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto""s thyroiditis, allergic disorders, including, but not limited to asthma, and allogeneic immune reponses, including, but not limited to, organ transplants or tissue grafts.
The cysteine protease inhibitory activities of the compounds of the invention can be determined by methods known to those of ordinary skill in the art. Suitable in vitro assays for measuring protease activity and the inhibition thereof by test compounds are known. Typically, the assay measures protease induced hydrolysis of a peptide based substrate. Details of assays for measuring protease inhibitory activity are set forth in Examples 7, 8, 9 and 10, infra.
The compounds of Formula I and the intermediates and starting materials used in their preparation are named in accordance with IUPAC rules of nomenclature in which the characteristic groups have decreasing priority for citation as the principle group as follows: acids, esters, amides, etc. For example, a compound of Formula I in which X1 is a divalent group of Formula (a), wherein X2 is xe2x80x94C(O)xe2x80x94, R7 is isobutyl and R5 and R9 both are hydrogen; R1 is benzyloxycarbonyl; R2 is hydrogen; R3 is phenethyl; and R4 is methoxymethyl; that is, a compound having the following structure: 
is named benzyl 1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)-3-methylbutylcarbamate; and a compound of Formula I in which X1 is a divalent group of Formula (a), wherein X2 is xe2x80x94C(O)xe2x80x94, R7 is isobutyl and R5 and R9 both are hydrogen; R1 is benzyloxycarbonyl; R2is hydrogen; R3 is phenethyl; and R4 is 2,5-dichlorobenzoyl; that is, a compound having the following structure: 
is named 3S-(2S-benzyloxycarbonylamino-4-methylpentanoylamino)-2-oxo-5-phenylpenyl 2,5-dichlorobenzoate; and a compound of Formula I in which X1 is a divalent group of Formula (a), wherein X2 is xe2x80x94C(O)xe2x80x94, R7 is 1-methylpropyl and R5 and R9 both are hydrogen; R1 is 3-aminomethylbenzoyl; R2 is hydrogen; R3 is phenethyl; and R4 is hydroxymethyl; that is, a compound having the following structure: 
is named 3-aminomethyl-N-[1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)-2-methylbutyl]benzamide.
In general, compounds of Formula I will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. For example, therapeutically effective amounts of a compound of Formula I may range from 0.1 micrograms per kilogram body weight (xcexcg/kg) per day to 10 milligram per kilogram body weight (mg/kg) per day, typically to 1 xcexcg/kg/day to 1 mg/kg/day. Therefore, a therapeutically effective amount for a 80 kg human patient may range from 10 xcexcg/day to 100 mg/day, typically 0.1 mg/day to 10 mg/day. In general, one of ordinary skill in the art, acting in reliance upon personal knowledge and the disclosure of this Application, will be able to ascertain a therapeutically effective amount of a compound of Formula I for treating a given disease.
The compounds of Formula I can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous). Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient. Such excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, or the like). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols.
The amount of a compound of Formula I in the composition may vary widely depending upon the type of formulation, size of a unit dosage, kind of excipients and other factors known to those of skill in the art of pharmaceutical sciences. In general, a composition of a compound of Formula I for treating a given disease will comprise from 0.01%w to 10%w, preferably 0.3%w to 1%w, of active ingredient with the remainder being the excipient two or excipients. Preferably the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required. Representative pharmaceutical formulations containing a compound of Formula I are described in Example 11.
The compounds of Formula I can be administered alone or in combination with other compounds of Formula I or in combination with one or more other active ingredient(s). For example, the compounds of Formula I can be administered in combination with a therapeutically active amount of a bisphosphonic acid or acid ester derivative or any pharmaceutically acceptable salt thereof. Suitable bisphosphonic acids and acid ester derivatives include compounds corresponding to the following formula: 
wherein X11 is a bond or (C1-7)alkylene, each R43 independently is hydrogen or (C1-30)alkyl, R44 and R45 are selected independently from a group consisting of hydrogen, halo, optionally substituted (C1-30)alkyl, (C3-30)cycloalkyl, hetero(C5-30)cycloalkyl, optionally substituted (C6-10)aryl, hetero(C6-10)aryl, xe2x80x94NR46R46, xe2x80x94OR46, xe2x80x94SR46, wherein each R46 independently is hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, optionally substituted (C6-10)aryl, provided that both R44 and R45 are not selected from hydrogen or hydroxy when X11 is a bond; or R44 and R45 taken together form (C2-9)alkylene; wherein (C3-10)cycloalkyl includes adamantyl and the like, hetero(C5-10)cycloalkyl includes pyrrolidinyl and the like, (C6-10)aryl includes phenyl and naphthyl, and hetero(C6-10)aryl includes quinolyl, isoquinolyl, pyridyl, furyl, imidazolyl, imidazopyridyl and the like.
Instances wherein R44 and/or R45 are substituted (C1-30)alkyl may include, but are not limited to, (C1-30)alkyl substituted by hetero(C5 10)cycloalkyl, (C6-10)aryl, hetero(C6-10)aryl, xe2x80x94NR47R47, xe2x80x94OR47 and xe2x80x94SR47, wherein each R47 is independently hydrogen or (C6-10)alkyl; wherein hetero(C5-10)cycloalkyl includes pyrrolidinyl and the like, (C6-10)aryl includes phenyl and naphthyl, and hetero(C6-10)aryl includes quinolyl, isoquinolyl, pyridyl, furyl, imidazolyl, imidazopyridyl and the like. Suitable optionally substituted aryl groups include, but are not limited to, halo-substituted phenyl.
A non-limiting class of bisphosphonic acids and acid ester derivatives thereof suitable for administration in combination with compounds of Formula I include those in which R4 is selected from the group consisting of hydrogen, hydroxy or halo, and R45 is selected from the group consisting of optionally substituted (C1-30)alkyl, halo and xe2x80x94SR46, wherein R46 is (C1-10)alkyl or phenyl.
A non-limiting subclass of bisphosphonic acids and acid ester derivatives thereof suitable for administration in combination with compounds of Formula I include those in which R44 is selected from the group consisting of hydrogen, hydroxy and chloro and R45 is selected from the group consisting of optionally substituted (C1-30)alkyl, chloro and chlorophenylthio.
A non-limiting example of a bisphosphonic acid suitable for administration in combination with compounds of Formula I include that in which X11 is a bond, each R43 is hydrogen, R44 is hydroxy and R45 is 3-aminopropyl, namely 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (aka alendronic acid), or the monosodium trihydrate salt thereof, namely 4-amino-1-hydroxybutylidene-1,1-bisphosphonate monosodium trihydrate (aka alendronate monosodium trihydrate), described in U.S. Pat. No. 4,922,007, to Kieczykowski et al., issued May 1, 1990; U.S. Pat. No. 5,019,651, to Kieczykowski et al., issued May 28, 1991; U.S. Pat. No. 5,510,517, to Dauer et al., issued Apr. 23, 1996; U.S. Pat. No. 5,648,491, to Dauer et al., issued Jul. 15, 1997, all of which patents are incorporated by reference herein in their entirety.
Further non-limiting examples of bisphosphonic acids suitable for administration in combination with compounds of Formula I include the following:
cycloheptylaminomethylene-1,1-bisphosphonic acid (aka cimadronic acid), described in U.S. Pat. No. 4,970,335, to Isomura et al., issued Nov. 13, 1990;
1,1-dichloromethylene-1,1-diphosphonic acid (aka clodronic acid) and the disodium salt thereof, namely clodronate disodium, described in Belgium Patent 672,205 (1966) and J. Org. Chem 32, 4111 (1967);
1-hydroxy-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid (aka EB-1053);
1-hydroxyethylidene-1,1-diphosphonic acid (aka etidronic acid);
1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid (aka ibandronic acid), described in U.S. Pat. No. 4,927,814, issued May 22, 1990;
6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (aka neridronic acid);
3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid (aka olpadronic acid);
3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (aka pamidronic acid);
2-pyrid-2-ylethylidene-1,1-bisphosphonic acid (aka piridronic acid), described in U.S. Pat. No. 4,761,406;
1-hydroxy-2-pyrid-3-ylethylidene-1,1-bisphosphonic acid (aka risedronic acid);
4-chlorophenylthiomethylenebisphosphonic acid (aka tiludronic acid), described in U.S. Pat. No. 4,876,248, to Breliere et al., Oct. 24, 1989; and
1-hydroxy-2-(1H-midazol-1-yl)ethylidene-1,1-bisphosphonic acid (aka zoledronic acid); all of which patents and other documents referred to above are incorporated by reference herein in their entirety.
A non-limiting subclass of bisphosphonic acids suitable for administration in combination with compounds of Formula I include those selected from the group consisting of alendronic acid, cimadronic acid, clodronic acid, tiludronic acid, etidronic acid, ibandronic acid, risedronic acid, piridronic acid, pamidronic acid, zolendronic acid, pharmaceutically acceptable salts thereof, and mixtures thereof. A further example of a bisphosphonic acid suitable for administration in combination with compounds of Formula I is alendronic acid or a pharmaceutically acceptable salt thereof, and mixtures thereof. A further non-limiting example is alendronate monosodium trihydrate.
Compounds of Formula I can be administered in combination with a therapeutically active amount of an estrogen receptor agonist. Non-limiting examples of estrogen receptor agonists suitable for administration in combination with the compounds of Formula I include naturally occurring estrogens such as estradiol, estrone and estroil, or synthetic estrogen receptor agonists such as [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-(2-piperidin-1-ylethoxy)phenyl]methanone (aka raloxifene) and {2-[4-(1,2-diphenylbut-1-enyl)phenoxy]ethyl}dimethylamine (aka tamoxifen). A non-limiting subclass of estrogen receptor agonists suitable for administration in combination with the compounds of Formula I include estrogen receptor partial agonists (i.e., estrogen receptor agonists with mixed agonist/antagonist properties), sometimes referred to as estrogen receptor modulators. Estrogen receptor partial agonists can exert tissue-selective estrogen agonist effects. Tamoxifen, for example, selectively exerts an estrogen agonist effect on the bone, in humans. Additional suitable estrogen receptor partial agonists are described in Tissue-Selective Actions Of Estrogen Analogs, Bone Vol. 17, No. 4, October 1995, 181S-190S. Certain 3-[4-(2-phenylindol-1-ylmethyl)phenyl]acrylamides, described in U.S. Pat. No. 5,985,910 to Miller et al., Nov. 16, 1999; benzothiphene compounds, described in U.S. Pat. No. 5,985,897 to Meuhl et al., Nov. 16, 1999; naphthyl compounds, described in U.S. Pat. No. 5,952,350 to Cullinan et al., Sep. 14, 1999; substituted benzothiophene compounds, described in U.S. Pat. No. 5,962,475 to Schmid et al., Oct. 4, 1999, are suitable estrogen receptor partial agonists for administration with the compounds of Formula I; all of which patents and other documents referred to above are incorporated by reference herein in their entirety.
More particularly a pharmaceutical composition of this invention may comprise a therapeutically effect amount of a compound of Formula I in combination with one or more active ingredient(s) selected from the group consisting of (i) a therapeutically effect amount of a bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effect amount of an estrogen receptor agonist or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipient(s). Non-limiting examples of such bisphosphonic acids include 1,1-dichloromethylene-1,1-diphosphonic acid, 1-hydroxy-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid, 1-hydroxyethylidene-1,1-diphosphonic acid, 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid, 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid, 3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid, 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid, 2-pyrid-2-ylethylidene-1,1-bisphosphonic acid, 1-hydroxy-2-pyrid-3-ylethylidene-1,1-bisphosphonic acid, 4-chlorophenylthiomethylenebisphosphonic acid and 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof; particularly 1,1-dichloromethylene-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof and preferably 1,1-dichloromethylene-1,1-diphosphonate monosodium trihydrate.
Processes for Making Compounds of Formula I:
Compounds of Formula I in which R4 is nitromethyl or xe2x80x94CH2OR18 can be prepared by proceeding as in the following Scheme 1: 
in which L is a leaving group, R20 is xe2x80x94OR22, wherein R22 is a hydroxy protecting group or optionally substituted (C1-6)alkyl, (C6-12)aryl(C0-6)alkyl, heteropolycyclo(C8-12)aryl(C0-6)alkyl, (C1-6)alkylcarbonyl or (C6-12)arylcarbonyl, R21 is R1 or a protecting group and each X1, R1, R2 and R3 are as defined in the Summary of the Invention for Formula I.
Compounds of Formula I in which R14is nitromethyl or xe2x80x94CH2OR18 (Formula I(a)) can be prepared by condensing a compound of Formula 2 with a compound of the formula LX1R21, and then removing one or more protecting groups if necessary. The compound of Formula 2 may be in a free base or an acid addition salt form, preferably an acid addition salt form (e.g., p-toluenesulfonic acid salt, or the like). Typically the condensation reaction is carried out under nitrogen in the presence of a suitable condensing agent (e.g., isobutyl chloroformate, or the like), a base (e.g., 4-methylmorpholine, triethylamine, or the like) and a suitable solvent (e.g., tetrahydrofuran (THF), or the like), at xe2x88x9220 to 0xc2x0 C., preferably at about xe2x88x9210xc2x0 C., and requires 45 minutes to 4 hours to complete. A detailed description of the condensation reaction is found in Example 2, infra. Deprotection can be effected by any means which removes the protective group and gives the desired product in reasonable yield. A detailed description of a deprotection procedure is found in Example 3, infra.
Compounds of Formula I in which R4 is xe2x80x94CH2OR18 can be prepared by proceeding as in the following reaction Scheme 2: 
in which L is a leaving group, R22 is a hydroxy protecting group or optionally substituted (C1-6)alkyl, (C6-12)aryl(C0-6)alkyl, heteropolycyclo(C8-12)aryl(C0-6)alkyl, (C1-6)alkylcarbonyl or (C6-12)arylcarbonyl, R20 is R1 or a protecting group and each X1, R1, R2, R3 and R17 are as defined in the Summary of the Invention for Formula I.
Compounds of Formula I in which R4 is xe2x80x94CH2OR18 (Formula I(b)) can be prepared by condensing a compound of Formula 3 with a compound of the formula LCH2OR22 and then removing one or more protecting groups if necessary. Typically the condensation reaction is carried out under nitrogen in a suitable solvent (e.g., THF) at xe2x88x9260 to 25xc2x0 C. and requires 10 to 20 hours to complete. A detailed description of the preparation of a compound of Formula I(c) is found in Example 1, infra.
Compounds of Formula I in which R4 is 1-hydroxy-1-methylethyl can be prepared by proceeding as in the following reaction Scheme 3: 
in which R21 is R1 or a protecting group and each X1, R1, R2 and R3 are as defined in the Summary of the Invention for Formula I.
Compounds of Formula I in which R4 is 1-hydroxy-1-methylethyl (Formula I(c)) can be prepared by oxidizing a compound of Formula 4 and then deprotecting if necessary. Typically the oxidation is carried out with a suitable oxidizing agent (e.g., Dess-Martin periodinate, or the like) in a suitable solvent (e.g., methylene chloride, or the like) at 15 to 25xc2x0 C. and requires 10 to 20 hours to complete. A detailed description of the preparation of a compound of Formula I(c) is found in Example 4, infra.
Compounds of Formula I in which R4 is nitromethyl can be prepared by proceeding as in the following Scheme 4: 
in which R21 is R1 or a protecting group and each X1, R1, R2 and R3 are as defined in the Summary of the Invention for Formula I.
Compounds of Formula I in which R4 is nitromethyl (Formula I(d)) can be prepared by reacting a compound of Formula 5 with nitromethane and then deprotecting if necessary. Typically the reaction with the nitromethane is carried out under nitrogen in the presence of a coupling agent (e.g., 1,1xe2x80x2-carbonyldiimidazole, or the like) and in a suitable solvent (e.g., TBF) at xe2x88x9210 to 25xc2x0 C. and requires 10 to 20 hours to complete.
Additional Processes for Preparing Compounds of Formula I:
A compound of Formula I can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of Formula I can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of Formula I are set forth in the definitions section of this application. Alternatively, the salt forms of the compounds of Formula I can be prepared using salts of the starting materials or intermediates.
The free acid or free base forms of the compounds of Formula I can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of Formula I in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, or the like). A compound of Formula I in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
The N-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as methylene chloride) at approximately 0xc2x0 C. Alternatively, the N-oxides of the compounds of Formula I can be prepared from the N-oxide of an appropriate starting material.
Compounds of Formula I in unoxidized form can be prepared from N-oxides of compounds of Formula I by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80xc2x0 C.
Prodrug derivatives of the compounds of Formula I can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters. 4:1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, or the like).
Protected derivatives of the compounds of Formula I can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protective groups and their removal can be found in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc. 1981.
Compounds of Formula I can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diasteromeric derivatives of compounds of Formula I, dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, and the like) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, Honh Wiley and Sons, Inc. (1981).
In summary, an aspect of this invention is a process for preparing a compound of Formula I, which process comprises:
(A) reacting a compound of Formula 2: 
with a compound of the formula LX1R21, in which L is a leaving group, R20 is xe2x80x94NO2 or xe2x80x94OR22, wherein R22 is a hydroxy protecting group or optionally substituted (C1-6)alkyl, (C6-12)aryl(C0-6)alkyl, heteropolycyclo(C8-12)aryl(C0-6)alkyl, (C1-6)alkylcarbonyl or (C6-12)arylcarbonyl, R21 is R1 or a protecting group and each X1, R1, R2 and R3 are as defined in the Summary of the Invention for Formula I, and then removing one or more protective groups if necessary to provide a compound of Formula I in which R4 is nitromethyl or xe2x80x94CH2OR17;
(B) reacting a compound of Formula 3: 
with a compound of the formula LCH2OR22, in which L is a leaving group, R22 is a hydroxy protecting group or optionally substituted (C1-6)alkyl, (C6-12)aryl(C0-6)alkyl, heteropolycyclo(C8-12)aryl(C0-6)alkyl, (C1-6)alkylcarbonyl or (C6-12)arylcarbonyl, R20 is R1 or a protecting group and each X1, R1, R2, R3 and R17 are as defined in the Summary of the Invention for Formula I, and then removing one or more protective groups if necessary to provide a compound of Formula I in which R4 is xe2x80x94CH2OR17;
(C) oxidizing a compound of Formula 4: 
in which R21 is R1 or a protecting group and each X1, R1, R2 and R3 are as defined in the Summary of the Invention for Formula I, and then deprotecting if necessary to provide a compound of Formula I in which R4 is 1-hydroxy-1-methylethyl;
(D) reacting a compound of Formula 5: 
with nitromethane, in which R21 is R1 or a protecting group and each X1, R1, R2 and R3 are as defined in the Summary of the Invention for Formula I, and then deprotecting if necessary to provide a compound of Formula I in which R4 is nitromethyl;
(E) optionally dealkylating a compound of Formula I in which R4 is xe2x80x94CH2OR18, wherein R18 is (C1-6)alkyl or (C6-12)aryl(C1-6)alkyl to provide a compound of Formula I in which R18 is hydrogen;
(F) optionally converting a compound of Formula I into a pharmaceutically acceptable salt;
(G) optionally converting a salt form of a compound of Formula I to non-salt form;
(H) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide;
(I) optionally converting an N-oxide form of a compound of Formula I its unoxidized form;
(K) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and
(L) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form.
Processes for Making the Intermediates used in Making Compounds of Formula I:
Compounds of Formula 2 in which R20 is xe2x80x94OR22 can be prepared by condensing an xcex1-aminoketone of Formula 6: 
in which L is a leaving group and R23 is an amino protective group, with a compound of the formula HOR22 and then selectively removing the amino protective group. The condensation reaction is carried out in the presence of potassium fluoride and a suitable solvent (N,N-dimethylformamide (DMF), or the like) at 20 to 30xc2x0 C., preferably at about xe2x88x9225xc2x0 C., and requires 1 to 3 hours to complete. The xcex1-aminoketone of Formula 3 is prepared from a corresponding xcex1-amino-xcex1xe2x80x2-diazoketone derivative. For example, a compound of Formula 3 in which L is bromo is prepared by treating a corresponding xcex1-amino-xcex1xe2x80x2-diazoketone derivative with hydrogen bromide in a suitable solvent (e.g., ether, or the like) at xe2x88x9220 to 0xc2x0 C., typically at about xe2x88x9210xc2x0 C., and requires approximately 30 minutes to 1 hour to complete. The xcex1-amino-xcex1xe2x80x2-diazoketone derivative is prepared by treating a corresponding xcex1-aminocarboxylic acid with diazomethane in the presence of a suitable condensing agent (e.g., isobutyl chloroformate, or the like) and base (e.g., 4-methylmorpholine, triethylamine, or the like) and in a suitable solvent (e.g., tetrahydrofuran (THF), or the like) at xe2x88x9210 to 0xc2x0 C., preferably at about xe2x88x9210xc2x0 C., and requires approximately 30 minutes to complete. Deprotection is conveniently effected by treating the protected intermediate with acid (e.g., p-toluenesulfonic acid) to provide the compound of Formula 2 in an acid addition salt form.
Compounds of Formula 2 in which R20 is xe2x80x94OR22 can be prepared by condensing a xcex1-amino-N-methoxy-N-methylcarboxamide of Formula 7: 
in which R23 is an amino protective group, with a compound of the formula LCH2OR22 and then selectively removing the amino protective group. Typically the reaction is carried out under nitrogen in a suitable solvent (e.g., THF) at xe2x88x9260 to 25xc2x0 C. and requires 10 to 20 hours to complete. Compounds of Formula 7 are prepared by reacting a corresponding xcex1-aminocarboxylic acid with N,O-dimethylhydroxylamine hydrochloride.
Compounds of Formula 2 in which R20 is xe2x80x94NO2 can be prepared by reacting a xcex1-aminocarboxylic acid of Formula 8: 
in which R23 is an amino protective group, with nitromethane and then selectively removing the amino protecting group. Typically the reaction with the nitromethane is carried out under nitrogen in the presence of a coupling agent (e.g., 1,1xe2x80x2-carbonyldiimidazole, or the like) and in a suitable solvent (e.g., TBF) at xe2x88x9210 to 25xc2x0 C. and requires 10 to 20 hours to complete. Detailed descriptions for the preparation of compounds of Formula 2 are found in References 1, 2 and 3, supra.
Compounds of Formula 3 are prepared by reacting a corresponding carboxylic acid with N,O-dimethylhydroxylamine hydrochloride. Compounds of Formula 4 can be prepared by oxidizing a corresponding N-(3-methylbut-2-enyl) derivative. Typically the oxidation of the N-(3-methylbut-2-enyl) derivative is carried out with a suitable oxidizing agent (e.g., osmium tetroxide, or the like) in a suitable solvent (e.g., acetonitrile, or the like) at approximately 0xc2x0 C. and requires 10 to 20 hours to complete. The N-(3-methylbut-2-enyl) derivative is prepared from a corresponding N-(2-oxoethyl) derivative via a Wittig reaction.
Process for Making Compounds of Formula II:
A process for preparing a compound of Formula II: 
which process comprises hydrogenating a compound of Formula 9: 
in which R1 is peptidyl, R2 is hydrogen or (C1-6)alkyl, R3 is an amino acid side chain and R4 is (C1-6)alkyl or (C6-12)aryl(C1-6)alkyl, in the presence of a catalytic amount of 20% palladium hydroxide on carbon. The hydrogenation can be effected with hydrogen gas or an effective amount of cyclohexene. The hydrogenation may be carried out in cyclohexene alone or along with a suitable solvent (e.g., ethanol, or the like) at 80 to 90xc2x0 C. and requires 1 to 2 hours to complete. Preferably, the process is carried out in an excess amount of cyclohexene, typically 100 times the molar amount of the compound of Formula II, in a 1:2 mixture of cyclohexene:ethanol. The process is particularly useful in preparing the individual (R)- or (S)-isomers of the compounds of Formula II. Thus, by proceeding as set forth above, the individual isomers of the compounds of Formula I in which R4 is hydroxymethyl can be prepared by dealkylating a compound of Formula I in which R1 is xe2x80x94CH2OR18, wherein R18 is (C1-6)alkyl or (C6-12)aryl(C1-6)alkyl. A detailed description of this process is found in Example 5, infra.